Notch signaling plays a key role in cardiac cell differentiation

Abstract

Results from lineage tracing studies indicate that precursor cells in the ventricles give rise to both cardiac muscle and conduction cells. Cardiac conduction cells are specialized cells responsible for orchestrating the rhythmic contractions of the heart. Here, we show that Notch signaling plays an important role in the differentiation of cardiac muscle and conduction cell lineages in the ventricles. Notch1 expression coincides with a conduction marker, HNK-1, at early stages. Misexpression of constitutively active Notch1 (NIC) in early heart tubes in chick exhibited multiple effects on cardiac cell differentiation. Cells expressing NIC had a significant decrease in expression of cardiac muscle markers, but an increase in expression of conduction cell markers, HNK-1, and SNAP-25. However, the expression of the conduction marker connexin 40 was inhibited. Loss-of-function study, using a dominant-negative form of Suppressor-of-Hairless, further supports that Notch1 signaling is important for the differentiation of these cardiac cell types. Functional studies show that the expression of constitutively active Notch1 resulted in abnormalities in ventricular conduction pathway patterns.

Cardiopoietic Factors

“…235 Likewise, a Notch2 pathway regulates Hey1-dependent downregulation of Bmp2, delimiting chamber from nonchamber myocardium in the AV canal. 236 …”

Isolation, Characterization and Differentiation Potential of Cardiac Progenitor Cells in Adult Pigs

“…These include Notch, which is responsible for the differentiation of various cell types of the ventricle. Notch acts on the cardiac progenitors by inhibiting the expression of heart muscle proteins and activating the expression of markers characteristic of conduction cells, such as SNAP25 and HNK1 (Chau et al 2006).…”

Cardiomyogenic stem and progenitor cell plasticity and the dissection of cardiopoiesis

“…Activation of Notch signaling pathway inhibits cardiac differentiation and, conversely, inhibition of Notch in heart promotes myogenesis, suggesting that Notch has suppressive effects on cardiac differentiation [166]. Indeed, Nemir et al have shown that Notch signaling is a critical regulator of CM differentiation.…”

“…Moreover, Srivastava's group have shown that Delta-1, a ligand of Notch, is a target of a micro RNA that regulates differentiation of cardiac progenitor cells, indicating that Notch signaling might play a role in differentiation of cardiac progenitor cells [170]. Forced expression of Notch1 in the ventricular cells also inhibits the expression of cardiac muscle markers, sarcomeric myosin heavy chain and α-actin, but increases the expression of conduction cell markers, HNK-1 and SNAP-25, suggesting that Notch signaling also regulates the cardiac cell type specification [166].…”